The following two methods are known as methods for producing polyhydroxycarboxylic acids by polymerizing hydroxycarboxylic acids such as lactic acid and glycolic acid: one is ring-opening polymerization of cyclic dimers of hydroxycarboxylic acids such as lactide and glycolide, and the other of direct dehydration condensation of hydroxycarboxylic acids.
As an example of the process which involves ring-opening polymerization of cyclic dimers of hydroxycarboxylic acids, Japanese Published Examined Patent Application No. 14688/81 discloses a process for producing copolymers of lactic acid and glycolic acid having an average molecular weight of 72,000 by copolymerizing, in the presence of stannous octanoate, a mixture of lactide and glycolide respectively obtained by dehydration polycondensation of lactic acid and glycolic acid. Japanese Published Unexamined Patent Application No. 69553/90 discloses polylactic acids and polyglycolic acids having molecular weights of 10,000-800,000, and also discloses, as an example of polylactic acid synthesis, a process for producing polylactic acids of molecular weights of 100,000 by subjecting DL-lactide to ring-opening polymerization in the presence of stannous octanoate catalyst.
Polyhydroxycarboxylic acids of high molecular weights can be obtained by these processes that involve ring-opening polymerization of cyclic dimers of hydroxycarboxylic acids. However, such processes have various problems for industrial utilization; that is, they are complicated with many steps, the yield of polymers produced is low, and the cost rises as a result.
On the other hand, processes by direct dehydration polycondensation of hydroxycarboxylic acids are industrially advantageous with fewer steps, high yield and low cost. However, these processes are not applicable to the production of polyhydroxycarboxylic acids of high molecular weights. As an example of the improved process of this direct dehydration condensation, Japanese Published Unexamined Patent Application No. 28521/86 discloses a process for producing polymers or copolymers of lactic acid and glycolic acid having a weight-average molecular weight of more than 5, 000, usually 5,000-30,000, by subjecting lactic acid and/or glycolic acid to polycondensation reaction in the presence or absence of an inorganic solid acid catalyst such as acid clay, activated clay, bentonite, kaolin, talc, aluminum silicate, magnesium silicate, aluminum borate, or silicic acid.
The weight-average molecular weight of the polymers or the copolymers produced by said process is around 30,000 at most. Even polymers or copolymers of weight-average molecular weight at such level may be considered to be satisfactory in physical properties as polymers to be used in bioabsorbable pharmaceutical compositions which are objective of said process, but they are dissatisfactory in physical properties as biodegradable plastics. Japanese Published Examined Patent Application No. 52930/90 discloses a process for producing polylactide having a molecular weight of at least 4,000, usually 4,000-20,000 by subjecting lactic acid to polycondensation reaction in the absence of a catalyst at a temperature of 220-260.degree. C. and at a pressure of less than 10 mmHg. Japanese Published Examined Patent Application No. 13963/93 discloses a process for producing polyglycolide or polylactide having a molecular weight of 8,000-11,000 by adding a phosphoric acid compound or a phosphorous acid compound when the molecular weight of lactic acid or glycolic acid subjected to polycondensation reaches 2,000-6,000 in the presence of a tin compound.
Japanese Published Unexamined Patent Application No. 65360/94 discloses a process for producing of polyhydroxycarboxylic acids having a weight-average molecular weight of more than 15,000, usually 5,000-200,000, by subjecting hydroxycarboxylic acids or oligomers thereof to dehydration polycondensation reaction in a reaction mixture containing an organic solvent substantially in the absence of water.
In this process, a catalyst is not necessarily used, but the use of a catalyst can accelerate the reaction. Metals belonging to II, III, IV, and V groups of the periodic table, and oxides or salts thereof are mentioned as catalysts. The use of an organic solvent in the reaction necessitates an additional complicated step to distil the organic solvent in this process.
Polymer Preprints, Japan, Vol. 44, No. 12, p. 3146-3147 (issued on Sep. 1, 1995) discloses a method for olycondensation of 90% L-lactic acid by the use of repolymers (weight-average molecular weight: 10,000-50,000) synthesized in the presence of stannous chloride. In this method, the molecular weight of polymers produced can be increased by introducing lactide into the reaction system, and the polycondensation reaction can be accelerated by using a solvent such as diphenyl ether to efficiently remove the water formed.
WO 95/28432 discloses a method for producing polyhydroxycarboxylic acids having a weight-average molecular weight of 50,000 or above by subjecting hydroxycarboxylic acids or oligomers thereof to polycondensation in the presence of aluminum silicate containing aluminum oxide in an amount of 5-40 wt %. This method does not use an organic solvent, but it takes a lot of time to produce polyhydroxycarboxylic acids of high molecular weight.
As described above, none of the prior art teaches a method for producing polyhydroxycarboxylic acids having a weight-average molecular weight of 50,000 or above in high yield in a short time by direct dehydration polycondensation of hydroxycarboxylic acids or oligomers thereof.